Abstract Background Differences in body composition during childhood can influence long-term health, with notable links to cardiometabolic disorders in later life. While genetic associations with body composition traits are well-studied, less is known about the role of epigenetic mechanisms, particularly in low- and middle-income countries where the burden of cardiometabolic disease is high. We investigated links between DNA methylation and three compartments of body composition: fat mass, lean mass, and bone measures using data from children enrolled in the Epigenetic Mechanisms linking Pre-conceptional nutrition and Health Assessed in India and Sub-Saharan Africa (EMPHASIS) study. Results We conducted an epigenome-wide association study of 11 body composition traits assessed through dual-energy X-ray absorptiometry in children from India (mean [range] age = 5.8 [5–7] years; n = 686) and The Gambia (age = 9.0 [7–9] years; n = 284), with blood DNA methylation measured at ~ 800,000 CpGs sites on the Illumina EPIC array. Cohort-specific analysis identified 8 unique differentially methylated CpGs associated with traits across all three body composition compartments ( p < 3.6 × 10 –8 ), with none overlapping both cohorts. Cross-cohort meta-analysis revealed four CpGs associated with lean mass and bone area mapping to SOCS3 and ZBTB16 . Region-level analyses identified 29 differentially methylated regions (DMRs) in India and 18 in The Gambia. 29 DMRs were identified in the meta-analysis, 25 of which were not detected in either cohort individually. Many DMRs were associated with more than one body composition trait. Conclusion We report novel DNA methylation signatures associated with body composition traits in children from two low- and middle-income countries. Identified loci map to genes linked to inflammatory signalling, energy metabolism and cellular stress response pathways, highlighting a potential role for epigenetic mechanisms in shaping early-life body composition.

Iron is essential for both humans and pathogens, yet its genetic regulation remains understudied in African populations. Here, we report genome-wide association studies of six iron-related biomarkers in 3928 children from five sites across Africa, with replication in 2868 African American adults and investigate associations with severe malaria and bacteremia. We identify previously unreported loci at genome-wide significance, for transferrin at GTF3C5, and for hepcidin at CHCHD7/SDR16C5. Variants tagging the DUP4 haplotype, encoding the Dantu blood group (rs552439837) are associated with soluble transferrin receptor levels. Variants at GTF3C5 (rs2905094) and DUP4 confer protection against severe malaria and bacteremia. The CHCHD7/SDR16C5 variant (rs73596248) increases hepcidin levels and is associated with reduced risk of Klebsiella pneumoniae and Staphylococcus aureus bacteremia. Polygenic risk scores derived from European data show limited transferability to African populations. In this work, we demonstrate new genetic insights into iron regulation and highlight iron's role in host-pathogen interactions.

BACKGROUND:Estimation of the nutrient requirements of young infants is often based on the population average intake from breastmilk on the assumption that milk must have evolved as the ideal food. This is a contestable assumption for some nutrients (especially iron). Additionally, whilst an average intake might suffice for an average infant there is considerable variation in milk composition. SUMMARY:This review considers how levels of the major nutritional components of breastmilk vary according to the mother's diet, her own nutritional status and whether she takes supplements. Several broad statements can be made: (a) the proximate composition of milk (protein, fat, and carbohydrate) is relatively insensitive to maternal nutrition although the fatty acid profile of milk does vary with maternal diet; (b) most water-soluble vitamins in milk closely follow maternal intake and status at least over the mid-range and are readily increased by supplementing the mother; folate is an exception; (c) the fat-soluble vitamins (A, D, K) are moderately sensitive to diet and can be altered by high-dose supplements; vitamin E is an exception; (d) milk iodine and selenium levels are sensitive to diet and hence show large geographical variations according to soil levels; the other minerals are virtually unaffected by diet or supplements. New estimates of milk composition have recently been published based on analysis of milk from healthy, well-nourished mothers in 4 counties and these will act as reference "target" values into the future. KEY MESSAGES:Broadly speaking, human milk has evolved to meet an infant's requirements but this might not always be the case as breastmilk composition can vary widely between mothers for some nutrients. Protein and carbohydrate (mostly in the form of lactose) in breastmilk tend to be unaffected by the mother's nutritional status. Fat content is very variable and is somewhat influenced by the mother's BMI. The fatty acid profile is strongly influenced by the mother's diet. Water-soluble vitamins reflect the mother's diet and can be increased by supplementation of the mother. Most minerals in milk are not related to the mother's status; the exceptions are iodine and selenium whose levels vary by geography according to the soil content of each mineral. New reference values for breastmilk nutrient levels and intakes from the MILQ Study have been published in 2025.

Objective:To estimate the associations between gestational weight gain and maternal immediate perinatal and postpartum outcomes by pooling data from low and middle income countries. Design:Individual participant data meta-analyses. Data sources:PubMed, Embase, Web of Science, and Cochrane Library, based on three searches (Search 1: all prospective studies published from January 2000 to May 2021; Search 2: randomized controlled trials of balanced energy and protein supplementation published until June 2021; Search 3: randomized controlled trials of anti-infectious agents published until August 2021). Eligibility criteria for selecting studies:Prospective studies (randomised controlled trials or observational cohort studies) with measured maternal weight during pregnancy and data available on maternal height, based in populations from low and middle income countries with no underlying conditions. Results:The analyses included 156 300 women from 61 studies and 23 countries, with most participants based in South Asia (n=78 454, 50.2%) and sub-Saharan Africa (n=36 327, 23.2%). Compared with women with adequate (90-125%) gestational weight gain, women with excessive (>125%) gestational weight gain had a higher risk of caesarean delivery (risk ratio 1.10, 95% confidence interval 1.06 to 1.13, τ2=0.000) and emergency caesarean delivery (risk ratio 1.22, 1.03 to 1.43, τ2=0.000). Women with moderately (70% to <90%) or severely inadequate (<70%) versus adequate gestational weight gain had lower risks for caesarean delivery (risk ratio in women with moderately inadequate gestational weight gain 0.88, 95% confidence interval 0.84 to 0.92, τ2=0.004; risk ratio in women with severely inadequate gestational weight gain 0.82, 0.77 to 0.88, τ2=0.010) and emergency caesarean delivery (risk ratio in moderately inadequate gestational weight gain 0.82, 0.71 to 0.95, τ2=0.004; risk ratio in severely inadequate gestational weight gain 0.73, 0.56 to 0.96, τ2=0.103). Excessive versus adequate gestational weight gain was associated with higher postpartum weight retained at any time point (mean difference 2.00 kg, 95% confidence interval 1.49 to 2.50, τ2=1.317), whereas moderately and severely inadequate gestational weight gain were associated with lower retained weight compared with adequate gestational weight gain. Similar trends were found for postpartum body mass index. Severely inadequate gestational weight gain was associated with lower systolic and diastolic blood pressure at any time point post partum than adequate gestational weight gain. No associations were observed for other outcomes including postpartum depressive symptoms or breastfeeding. Evidence indicating an interaction between gestational weight gain and body mass index before pregnancy was found when examining the risk of caesarean delivery and postpartum weight retention, body mass index, and systolic blood pressure as outcomes. Conclusions:These findings support the association between suboptimal gestational weight gain and adverse maternal outcomes in the immediate perinatal and postpartum periods. Further research examining the consequences of suboptimal gestational weight gain in low and middle income countries would be valuable to inform potential strategies to improve long term maternal health. Review registration:PROSPERO CRD42023432836.

Community Health Workers (CHWs) are increasingly being involved in screening for hypertension in rural sub-Saharan Africa. However the diagnostic accuracy of CHW-led attended (CHW present during procedure) and unattended (CHW absent) automated blood pressure (BP) in home settings has not been compared. We conducted a cross-sectional, population-based diagnostic accuracy study in two health and demographic surveillance systems in Kenya and The Gambia. A random age-stratified sample of individuals aged ≥ 30 years were included. The index tests were attended and unattended automated BP measurements conducted by CHWs at participants’ homes (AHBP). The reference test, 24-hour ambulatory BP monitoring (ABPM), was also conducted by the CHWs. We applied BP cutoffs derived from the European Society of Hypertension to determine sensitivity, specificity, predictive values and area under receiver operating characteristic curve (AUC). We included 1220 participants (659 in Kenya and 561 in The Gambia). The median age was 54 years (interquartile range 43 years, 66 years) and 775 (63.5

BackgroundSmall vulnerable newborn (SVN) types, defined by combinations of being born too soon or too small, have distinct determinants, health consequences, and prevention strategies. The effects of prenatal balanced energy and protein (BEP) supplementation on SVN types remain unknown.Methods and findingsWe conducted a systematic review and meta-analysis of individual participant data from eight randomized controlled trials of prenatal BEP supplements (N = 10,252, with 5,164 in the BEP arm and 5,088 in the control arm) in low- and middle-income countries were used. The control arms varied across studies and included context-specific standards of care, iron and folic acid supplements, or multiple micronutrient supplements. Newborns were classified into 10 groups through the combinations of preterm birth, small for gestational age (SGA) birth, and low birthweight (LBW), such as term-appropriate-for-gestational-age (AGA)-nonLBW, preterm-SGA-LBW, preterm-large-for-gestational-age-LBW, term-SGA-LBW, preterm-AGA-nonLBW, and other permutations. Newborns were also analyzed using a four-group categorization that included term-nonSGA, preterm-nonSGA, term-SGA, and preterm-SGA. Log-binomial models were used to estimate study-specific risk ratios (RRs), which were pooled using meta-analyses. Subgroup analyses were conducted by maternal age, parity, gestational age at enrollment, early pregnancy body mass index, and maternal anemia status. In the 10-group categorization of SVNs, on average, prenatal BEP supplementation led to a 30% lower risk of preterm-SGA-LBW (RR: 0.70; 95% CI [0.53, 0.91]; P = 0.009), a 25% lower risk of preterm-AGA-LBW (RR: 0.75; 95% CI [0.60, 0.93]; P = 0.009), and a 20% lower risk of term-SGA-LBW (RR: 0.80; 95% CI [0.72, 0.90]; P < 0.001). In the four-group categorization, prenatal BEP supplementation led to a 31% lower risk of preterm-SGA (RR: 0.69; 95% CI [0.52, 0.91]; P = 0.008) and a 12% lower risk of term-SGA (RR: 0.88; 95% CI [0.81, 0.96]; P = 0.005). The protective effect of prenatal BEP supplementation on preterm-SGA was stronger among multiparous women and women without anemia. The protective effects on all three SVN types under the four-group categorization were stronger among women enrolled before 20 weeks of gestation. The main limitations of the study included the absence of some BEP trials and the small event numbers for some SVN types.ConclusionsPrenatal BEP supplementation reduces the risk of SVNs to varying extents. Further research is needed to determine the optimal targeting approach for providing BEP supplements to vulnerable pregnant women who are most likely to benefit from the supplementation.

Abstract At rare human genomic regions, DNA methylation states are established in the early embryo and maintained during cellular differentiation, yielding systemic (i.e. not tissue-specific) interindividual epigenetic variation. Previous screens for such correlated regions of systemic interindividual variation (CoRSIVs) were limited to White Americans. Here, we describe the first human CoRSIV screen including self-identified Black and White Americans. We integrate deep whole-genome bisulfite sequencing data for three tissues from each of ten Black and ten White donors in the NIH Genotype-Tissue Expression program. This approach identifies twice as many CoRSIVs among Black than White Americans. Establishment of CoRSIV methylation is sensitive to periconceptional environmental exposures including assisted reproduction, seasonal variation, and famine. CoRSIV-associated genes are enriched for GWAS variants linked to cancer and neurodevelopment. Although only 15% of Black CoRSIVs overlap with those among White individuals, both sets are associated with the same subfamilies of transposable elements. Within multiple cell lines, ranked enrichments of transcription factor binding to Black and White CoRSIVs are exquisitely coordinated and related to genome organization, indicating that CoRSIV methylation states established in the early embryo play an important role in guiding subsequent cellular differentiation.

Climate change has resulted in an increase in heat exposure globally. There is strong evidence that this increased heat stress is associated with poor maternal and fetal outcomes, especially in vulnerable populations. However, there remains poor understanding of the biological pathways and mechanisms involved in the impact of heat in pregnancy. This observational cohort study of 764 pregnant participants based in sub-Saharan Africa, a geographical region at risk of extreme heat events, aims to evaluate the physiological and biochemical changes that occur in pregnancy due to heat stress. The key objectives of the study are to 1) map exposure to heat stress in the cohort and understand what environmental, social and community factors increase the risk of extreme heat exposure; 2) assess the impact of heat stress on maternal health, e.g. heat strain, subjective psychological well-being, sleep and activity level; 3) evaluate how heat stress impacts placenta structure and function; 4) determine how chronic heat exposure impacts birth outcomes; and 5) explore the epigenetic changes in the placenta and infant by heat stress exposure per trimester. Pregnant women will be recruited from two distinct regions in The Gambia to exploit the naturally occurring heat gradient across the country. Microclimate mapping of the area of recruitment will give detailed exposure measurements. Participants will be asked to wear a watch-style device at 28- and 35-weeks gestational age to evaluate maternal heart rate, activity and sleep. At the end of the week, an ultrasound scan will be performed to evaluate fetal size and placental blood flow. At delivery, birth outcomes will be recorded and maternal, placental and cord samples taken for epigenetic, biochemical and histological evaluation. Evaluation of neuro-behaviour and final infant samples will be taken at 1 month following birth.

BACKGROUND:Supplementation with conventional ferrous salts has limited efficacy in controlling anemia and improving iron status in children at high risk of inflammation. We assessed whether heme iron polypeptide (HIP), an alternative form of supplemental iron with a distinct absorption pathway, might improve outcomes. OBJECTIVES:We compared hemoglobin and ferritin concentrations in anemic Gambian infants aged 6-12 mo after supervised daily oral supplementation with HIP or ferrous sulfate. METHODS:Between March 2023 and February 2024, 208 anemic infants, aged 6-12 mo (hemoglobin, 7.0 to <11.0 g/dL) were randomly assigned to 84 d of directly observed daily supplementation with 10 mg elemental iron as HIP or ferrous sulfate. Primary outcomes were hemoglobin and ferritin concentrations at end of intervention. Analysis was by intention-to-treat with multiple imputations to replace missing data. RESULTS:Adherence to treatments was ∼90%. The primary end points of hemoglobin and ferritin concentrations both improved by day 84 with no difference between treatments. For the secondary end point of anemia, the prevalence went from 83.7% to 46.2% in the ferrous sulfate group and from 84.6% to 47.1% in the HIP group. Infants who received HIP had higher serum iron concentration (by 48.4%; 95% CI: 15.4%, 91.0%), higher transferrin saturation (by 52.3%; 95% CI: 17.9%, 96.7%), lower soluble transferrin receptor concentrations (by -9.7%; 95% CI: -16.3%, -2.6%) and lower unsaturated iron-binding capacity (by -7.8%; 95% CI: -13.4%, -1.7%). In a post hoc analysis, HIP had a greater effect on inflammation-adjusted serum ferritin concentrations (by 22.9%; 95% CI: 5.6%, 43.1%). No group differences were found in the frequency of adverse events. CONCLUSIONS:There is no benefit of HIP on the primary end points of hemoglobin and ferritin. However, HIP is superior to ferrous sulfate for 5 secondary measures of iron status and might therefore improve iron supply to rapidly developing organs. This trial is registered with the Pan African Clinical Trial Registry as PACTR202210523178727 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=23910).

Aims:Obesity, type 2 diabetes (T2D), and chronic inflammation are associated with disturbances in iron metabolism. Hepcidin is hypothesized to play a role in these alterations owing to its strong association with inflammation via the JAK-STAT3 pathway. The current study investigated the differences between inflammatory markers and iron indices and their association with hepcidin in lean women, women with obesity, and women with obesity and T2D (obesity-T2D) in The Gambia. Materials and methods:In a cross-sectional study design, fasted blood samples were collected from three groups of women: lean women (n=42, geometric mean (GM) body mass index (BMI)=20.9 kg/m 2), women with obesity (n=48, GM BMI=33.1 kg/m 2) and women with obesity-T2D (n=30, GM BMI=34.5 kg/m 2). Markers of inflammation (IL-6 and CRP) and iron metabolism [hepcidin, iron, ferritin, soluble transferrin receptor (sTfR), transferrin, transferrin saturation, and unsaturated iron-binding capacity (UIBC)] were compared using linear regression models. Simple regression analyses were performed to assess the association between hepcidin levels and respective markers. Results:Women with obesity and obesity-T2D showed elevated levels of inflammatory markers. There was no evidence that markers of iron metabolism differed between lean women and obese women, but women with obesity-T2D had higher transferrin saturation, higher serum iron concentration, and lower UIBC. Serum hepcidin concentrations were similar in all the groups. Hepcidin was not associated with markers of inflammation but was strongly associated with all other iron indices (all P<0.002). Conclusion:Contrary to our original hypothesis, hepcidin was not associated with markers of inflammation in the three groups of Gambian women, despite the presence of chronic inflammation in women with obesity and obesity-T2D.

Climate change has resulted in an increase in heat exposure globally. There is strong evidence that this increased heat stress is associated with poor maternal and fetal outcomes, especially in vulnerable populations. However, there remains poor understanding of the biological pathways and mechanisms involved in the impact of heat in pregnancy. This observational cohort study of 764 pregnant participants based in sub-Saharan Africa, a geographical region at risk of extreme heat events, aims to evaluate the physiological and biochemical changes that occur in pregnancy due to heat stress. The key objectives of the study are to 1) map exposure to heat stress in the cohort and understand what environmental, social and community factors increase the risk of extreme heat exposure; 2) assess the impact of heat stress on maternal health, e.g. heat strain, subjective psychological well-being, sleep and activity level; 3) evaluate how heat stress impacts placenta structure and function; 4) determine how chronic heat exposure impacts birth outcomes; and 5) explore the epigenetic changes in the placenta and infant by heat stress exposure per trimester. Pregnant women will be recruited from two distinct regions in The Gambia to exploit the naturally occurring heat gradient across the country. Microclimate mapping of the area of recruitment will give detailed exposure measurements. Participants will be asked to wear a watch-style device at 28- and 35-weeks gestational age to evaluate maternal heart rate, activity and sleep. At the end of the week, an ultrasound scan will be performed to evaluate fetal size and placental blood flow. At delivery, birth outcomes will be recorded and maternal, placental and cord samples taken for epigenetic, biochemical and histological evaluation. Evaluation of neuro-behaviour and final infant samples will be taken at 1 month following birth.

Iron is an essential trace element for both humans and pathogens, but its genetic determinants are understudied in Africa where iron deficiency and infectious diseases are highly prevalent. We conducted genome-wide association studies for six iron-related biomarkers in 3928 children from five sites across Africa with replication in 2868 African American adults. We identify a previously-unreported loci for transferrin in GTF3C5, a gene regulating cellular iron-uptake, for soluble transferrin receptor in FREM3, the Dantu locus, and for hepcidin in CHCHD7/SDR16C5. The lead GTF3C5 and FREM3 variants, rs2905094, and rs141274959, were associated with protection against severe malaria and bacteremia in large case-control studies. The CHCHD7/SDR16C5 lead variant, rs73596248, increased hepcidin concentrations and protected against bacteremia. We report limited transferability of polygenic risk scores derived from European studies to African populations. Our findings advance the understanding of the genetics of iron status in Africa and suggest an important link between iron and infection. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by Wellcome (Grant numbers [224317 to JMM], [226014 to SHA], [202800 to TNW], [103951 to AOE], and [106289 to AJM] and Grant numbers [064693, 079110, 095778 to AME]) and with core awards to the KEMRI-Wellcome Trust Research Programme (203077), The Wellcome Centre for Human Genetics (090532, 203141) and the Wellcome Sanger Institute (098051, 206194). The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I) and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute on Minority Health and Health Disparities (NIMHD). The authors also wish to thank the staffs and participants of the JHS. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. JJG was funded by a National Institute for Health and Care Research Clinical Lectureship. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Individual study site ethical approvals were obtained. For Kilifi Kenya (by the Scientific Ethics Review Unit of the Kenya Medical Research Institute (KEMRI/SERU/CGMR-C/046/3257/2983)); Entebbe Uganda (locally by the Uganda Virus Research Institute (GC/127/12/07/32) and Uganda National Council for Science and Technology (MV625) and in the UK by the London School of Hygiene and Tropical Medicine (A340) and Oxford Tropical Research (OTR) (39-12, 42-14 and 37-15) Ethics Committees); Banfora, Burkina Faso (by Ministere de la Recherche Scientifique et de lInnovation in Burkina Faso (2014-12-151) and the OTR Ethics Committees (41-12)); Soweto South Africa (by the University of Witwatersrand Human Research (M130714) and the OTR Ethics Committees (1042-13 and 42-14)); and West Kiang The Gambia (by the Gambian Government / Medical Research Council Ethics Committee (874/830)). For JHS relevant data transfer agreements were signed. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data are available in the main text or the Supplementary Materials. All direct genotypes from individuals after QC along-side imputed data have been submitted to the European Genome-Phenome Archive under accession, with the datasets under EGAD00010002578 and EGAD00010002583 (Uganda); EGAD00010002582 and EGAD00010002580 (South Africa); EGAD00010002581 and EGAD00010002579 (Burkina Faso). Applications for access to primary individual level de-identified phenotype data for the Kilifi, Kenya; Entebbe, Uganda; Banfora, Burkina Faso; and West Kiang, The Gambia cohorts can be made through the Data Governance Committee cgmrc@kemri-wellcome.org.

Variable DNA methylation states during early embryonic development overlap with mechanisms of transposon silencing by Krüppel-associated box zinc finger proteins (KZFPs). We investigated the influence of genetic variation in KZFPs and their transposon targets and identified a variably methylated region (VMR) proximal to the human LY6S-AS1 gene linked to an intronic MER11C retrotransposon targeted by the primate-specific KZFP ZNF808. Mendelian randomisation analysis supported a causal link between VMR methylation and type 1 diabetes risk, and H1 stem cells with inactivated ZNF808 showed marked, transient upregulation of the LY6S-AS1 transcript during the early stages of pancreatic development. Loss of function genetic mutations in ZNF808 have previously been linked to pancreatic agenesis and neonatal diabetes in humans, and the VMR was previously associated with levels of insulin secretion in Gambian children. Together this evidence points to a link between KZFP-mediated DNA methylation of LY6S-AS1 , and pancreatic development and function at this locus. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by UK Medical Research Council grants MR/ T032863/1 and MC\_PC\_21037. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for all human data analysed in this study was given by the joint Gambia Government/Medical Research Council Unit The Gambia Ethics Committee. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

BACKGROUND:Five risk factors account for approximately 50% of the global burden of cardiovascular disease. How the presence or absence of classic risk factors affects lifetime estimates of cardiovascular disease and death from any cause remains unclear. METHODS:We harmonized individual-level data from 2,078,948 participants across 133 cohorts, 39 countries, and 6 continents. Lifetime risk of cardiovascular disease and death from any cause was estimated up to 90 years of age according to the presence or absence of arterial hypertension, hyperlipidemia, underweight and overweight or obesity, diabetes, and smoking at 50 years of age. Differences in life span (in terms of additional life-years free of cardiovascular disease or death from any cause) according to the presence or absence of these risk factors were also estimated. Risk-factor trajectories were analyzed to predict lifetime differences according to risk-factor variation. RESULTS:The lifetime risk of cardiovascular disease was 24% (95% confidence interval [CI], 21 to 30) among women and 38% (95% CI, 30 to 45) among men for whom all five risk factors were present. In the comparison between participants with none of the risk factors and those with all the risk factors, the estimated number of additional life-years free of cardiovascular disease was 13.3 (95% CI, 11.2 to 15.7) for women and 10.6 (95% CI, 9.2 to 12.9) for men; the estimated number of additional life-years free of death was 14.5 (95% CI, 9.1 to 15.3) for women and 11.8 (95% CI, 10.1 to 13.6) for men. As compared with no changes in the presence of all risk factors, modification of hypertension at an age of 55 to less than 60 years was associated with the most additional life-years free of cardiovascular disease, and modification of smoking at an age of 55 to less than 60 years was associated with the most additional life-years free of death. CONCLUSIONS:The absence of five classic risk factors at 50 years of age was associated with more than a decade greater life expectancy than the presence of all five risk factors, in both sexes. Persons who modified hypertension and smoking in midlife had the most additional life-years free of cardiovascular disease and death from any cause, respectively. (Funded by the German Center for Cardiovascular Research [DZHK]; ClinicalTrials.gov number, NCT05466825.).

The burden of hypertension is rising rapidly in sub-Saharan Africa (SSA), posing significant health challenges and economic costs that hinder national development. Despite being well-studied in clinical medicine, the detection, treatment, and control of hypertension in SSA remain inadequate. This is due to barriers across the care continuum, including individual-, provider-, and system-level obstacles within the health system. A critical issue is the lack of contextualized mechanistic research to understand the mechanisms, phenotypes, and treatment responses in native SSA populations. Current treatment approaches are often based on data from diaspora Africans, particularly African Americans. Consequently, most guidelines do not recommend angiotensin system drugs as first-line agents for Black patients, a stance that should be reconsidered given some evidence of their effectiveness in native SSA populations. Addressing these barriers requires a comprehensive, multisectoral strategy that includes both preventative and clinical measures at the population and individual levels. Preventative approaches should encompass health and nutrition education, improving food supply quality, and implementing comprehensive transportation and environmental policies. In addition, strategies should be developed to increase the detection of undiagnosed cases through enhanced screening and treatment access to those not receiving care, and revisit current treatment approaches to ensure that they are more tailored to the specific populations and settings. In conclusion, innovative strategies are needed to identify and overcome barriers to hypertension diagnosis and management. A coordinated, multisectoral approach that includes a contextualized mechanistic research agenda, as well as task shifting and task sharing, will help prevent and reduce hypertension in SSA.

Vitamin D deficiency is prevalent in Africa, but its genetic determinants are understudied. We report a genome-wide analysis of 25-hydroxyvitamin D (25(OH)D) concentrations in 3670 children from five countries across Africa with replication in four diaspora African ancestry populations (n=21,610). We identify a previously unreported locus at genome-wide significance in West African populations: OSBPL11 (Oxysterol Binding Protein Like 11, lead variant, rs2979356, p=8.01 × 10-9). In vitro and molecular docking assays showed that OSBPL11 is a vitamin D binding protein likely involved in the intracellular binding of vitamin D metabolites. OSBPL11 knockdown mice have increased fat, reduced triglycerides and improved glucose tolerance, and rs2979356 was associated with cardiometabolic health in adults of African ancestry. We also identify previously reported loci determining vitamin D status. Our study advances understanding of vitamin D genetics in Africa and indicates a novel function for OSBPL11 in intracellular binding and transport of vitamin D metabolites.

Although malnutrition in the form of child wasting, stunting, and micronutrient deficiencies remain prevalent on many of the poorest and war-torn places on earth, there has been major progress in other regions and the direction of travel remains generally good. However, as countries pass through the economic transition there has been a seemingly inevitable rise in overweight and obesity with its attendant personal health costs (reduced life span due to obesity-related chronic conditions) and a rise in the societal costs of care. Strategies, by healthcare professionals and others, to combat the two sides of the malnutrition coin must be built on a solid foundational knowledge of the causes of each condition. The individual, nutritional, and environmental drivers are summarized here. It is sometimes helpful to focus on a single unifying concept as a way of rationalizing the causes and required solutions; namely the nutrient density of foods. Malnutrition is caused, inter alia, by foods lacking in sufficient energy, protein, and micronutrients. The same is true for obesity which, in large part, is driven by foods overly dense in energy but lacking other critical nutrients. Food quality therefore emerges as a key concept that healthcare professionals can adopt as they educate parents and children at the microlevel and schools, health systems, and government bodies at the macrolevel.